Despite significant advances in surgery, radiation therapy and chemotherapy, the survival rates for oral cancer have not improved significantly over the past 30 years. Furthermore, ulceration, lack of salivary function, difficulties in chewing and eating are some of the significant side effects associated with current therapies. Development of new therapeutic approaches requires identification of agents that will affect growth of cancer cells without destroying adjacent healthy tissues. The long-term goal of this proposal is to develop a genetically altered protein which will inhibit growth of HPV-associated oral cancer cells without affecting growth of normal cells. Studies from several laboratories have shown that about 40 percent of oral cancers are linked to HPV infections. The expression of the E7 oncoprotein encoded by HPV is critical for development and maintenance of the HPV-associated cancers. Previous studies have also shown that an inhibiting E7 expression blocks growth of HPV-transformed oral keratinocytes. This proposal is based on our observations that the HPV oncoprotein E7 functionally associates with the S4 subunit of the 26S proteasome and induces a proteolytic degradation of the Rb tumor suppressor protein. We will investigate the hypothesis that inhibition of the E7/S4 interaction will block Rb-degradation and E7's ability to transform oral keratinocytes. The specific aims are to: 1) establish the role of the S4 in E7-induced immortalization of oral keratinocytes. 2) identify the minimal S4-peptide sequence that binds and inhibits function of E7. 3) generate a genetically altered S4 protein that will sequester E7 into a non-functional complex and will inhibit growth of HPV-transformed keratinocytes. The proposed studies will (1) elucidate the role of S4 in HPV-associated oral cancers and (2) generate S4-specific reagents that will be valuable in therapeutic interventions of oral cancers.